Interaction between Raf and Myc oncogenes in transformation in vivo and in vitro

Abstract

3611 MSV, a raf-oncogene-transducing murine retrovirus, induces fibrosarcomas and erythroid hyperplasia in newborn mice after a latency of 4–8 wk. In contrast, new recombinant murine retroviruses carrying the myc oncogene (J-3, J-5 construct viruses) do not induce tumors before > 9 wk. A combination of both oncogenes in an infectious murine retrovirus (J-2) induces hematopoietic neoplasms in addition to less prominent fibrosarcomas and pancreatic adenocarcinoma 1–3 wk after inoculation. The hematologic neoplasms consist of immunoblastic lymphomas of T and B cell lineage and erythroblastosis. If animals were inoculated with a variant of the J-3 virus, which induces altered foci in cultures of NIH 3T3 cells, carcinoma developed in the pancreas with a 2–6 mo latency. In parallel to the synergistic action of both oncogenes on hematopoietic cells in vivo, we find that raf-oncogene-induced transformation of bone marrow cells in culture is enhanced by the addition of myc, which by itself does not transform these cells when grown in standard media. We conclude that concomitant expression of raf and myc oncogenes in hematopoietic and epithelial cells alters their respective transforming activities. The contribution of v-myc in this synergism was examined by use of a series of recombinant murine retroviruses capable of expressing the avian v-myc to study the effect of altered myc expression on hematopoietic/lymphoid cells. With either interleukin 3- or interleukin 2-dependent cell lines, introduction of the recombinant viruses abrogated the requirement for IL 3 or IL 2 for growth, and associated with this was the suppression of c-myc expression. The findings suggest that myc is a component in the signal transduction pathway for IL 3 and IL 2 and support an autoregulatory mechanism of c-myc expression. In contrast to v-myc, expression of v-raf primary lymphoid hematopoietic cells has an immortilizing function without abrogating the requirement for IL 3 for growth. This suggests that v-raf and v-myc affect different components of growth regulation, as, for example, commitment (v-myc ) and cell cycle progression (v-raf).